Novel 3,5-dioxopyrazolidine derivatives

ABSTRACT

NOVEL 3,5-DIOXOPYRAZOLIDINE DERIVATIVES, HAVING EXCELLENT ANTI-INFLAMMATORY EFFECT AND REPRESENTED BY THE FORMULA I,   1-(R1-PHENYL),2-((R5,R6-PHENYL)-C(-R4)=C(-R3)-),3,5-   DI(O=),4-R2-PYRAZOLIDINE   WHEREIN R1 SIGNIFIES A HYDROGEN ATOM, A HALOGEN ATOM, A NITRO GROUP, A LOWER ALKYL GROUP, A LOWER ALKOXY GROUP; R2 SIGNIFIES AN ALKYL GROUP HAVING UP TO 6 CARBON ATOMS; R3 AND R4 EACH SIGNIFIES A HYDROGEN ATOM, A LOWER ALKYL GROUP, A PHENYL GROUP OR A SUBSTITUTED PHENYL GROUP; R5 AND R6 EACH SIGNIFIES A HYDROGEN ATOM, A HALOGEN ATOM, A NITO GROUP, A LOWER ALKYL GROUP, A LOWER ALKOXY GROUP, A HALOGENATED ALKY GROUP OR AN ALKYLATED AMINO GROUP; PROVIDED THAT R5 AND R6 MAY FORM AN OPTIONALLY 5- OR 6-MEMBERED HETEROCYCLIC RING TOGETHER WITH THE ADJACENT PHENYL GROUP, ARE PRODUCED BY CONTACTING A PHENYLHYDRAZONE DERIVATIVE REPRESENTED BY THE FORMULA II,   ((R1-PHENYL)-NH-N=C(-R3)-CH(-R4)-),R5,R6-BENZENE   WHEREIN R1, R3, R4, R5 AND R6 ARE AS DEFINED ABOVE WITH A MALONIC ACID DERIVATIVE REPRESENTED BY THE FORMULA III,   R2-CH(-COOH)2   WHEREIN R2 IS AS DEFINED ABOVE OR ITS REACTIVE DERIVATIVES OR REACTING THE PHENYLHYDRAZONE DERIVATIVE OF THE FORMULA II WITH AN ORGANIC ACID OF THE FORMULA IV   R7COOH   WHEREIN R7 REPRESENTS AN ALKYL GROUP HAVING UP TO 3 CARBON ATOMS, OR ITS REACTIVE DERIVATIVE, AND THEN CONTACTING THE RESULTING N1,N2-DIACYCLPHENYLHYDRAZINE DERIVATIVE OF THE FORMULA V,   ((R1-PHENYL)-N(-CO-R7)-N(-CO-R7)-C(-R3)=C(-R4)-),R5,R6-   BENZENE   WHEREIN R1, R3, R4, R5, R6 AND R7 ARE AS DEFINED ABOVE, WITH A MALONIC ACID DERIVATIVE OF THE FORMULA III.

United States Patent thee 3,703,513 Patented Nov. 21, 1972 Int. Cl. C0711 49/04 US. Cl. 260-240 D 3 Claims ABSTRACT OF THE DISCLOSURE Novel 3,5-dioxopyrazolidine derivatives, having excellent anti-inflammatory efiect and represented by the Formula I,

Ra Rs R2 i =e N wherein R signifies a hydrogen atom, a halogen atom, a nitro group, a lower alkyl group, a lower alkoxy group; R signifies an alkyl group having up to '6 carbon atoms; R and R each signifies a hydrogen atom, a lower alkyl group, a phenyl group or a substituted phenyl group; R and R each signifies a hydrogen atom, a halogen atom, a nitro group, a lower alkyl group, a lower alkoxy group, a halogenated alkyl group or an alkylated amino group; provided that R and R may form an optionally 5- or 6-membered heterocyclic ring together with the adjacent phenyl group, are produced by contacting a phenylhydrazone derivative represented by the Formula '11,

Re R5 Ra a 1 (II) wherein R R R R and R are as defined above with a malonic acid derivative represented by the Formula IH,

C O OH Rz-CH O O C H 1) wherein R represents an alkyl group having up to 3 carbon atoms, or its reactive derivative, and then contacting the resulting N ,N -diacylpheny1hydrazine derivative of the Formula V,

wherein R R R R R and R are as defined above, with a malonic acid derivative of the Formula III.

This invention relates to a novel process for producing 3,5-dioxopyrazolidine derivatives. More particularly, the invention pertains to a novel process for preparing 3,5-dioxopyrazolidine derivatives which are excellent in anti-inflammatory action and represented by the formula,

wherein R signifies a hydrogen atom, a halogen atom, a nitro group, a lower alkyl group, a lower alkoxy group; R signifies an alkyl group having 1 to 6- carbon atoms; R and R each signifies a hydrogen atom, a lower alkyl group, a phenyl group, or a substituted phenyl group; R and R each signifies a hydrogen atom, a halogen atom, a nitro group, a lower alkyl group, a lower alkoxy group, a halogenated alkyl group, or an alkylated amino group; provided that R and R may form an optionally 5- or 6- membered heterocyclic ring together with the adjacent phenyl group.

In the compound represented by the aforesaid Formula I, the halogen atom includes chlorine, bromine, iodine and fluorine atoms; the alkyl group includes straight chain or branched-chain groups; the lower alkyl group includes, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl and tertiary butyl groups; the lower alkoxy group includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and tertiary butoxy groups; and the halogenated alkyl group is preferably a trifluoromethyl group, for example. R represents a straight chain or branchedchain alkyl group having 1-6 carbon atoms, and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-amyl, isoamyl, and n-hexyl groups, and npropyl, n-butyl or n-amyl group is most preferable. In the case R and R form a heterocyclic ring condensed with the phenyl group, the heterocyclic group is, for example, methylene-dioxy group.

The present invention is further concerned with a process for producing 3,5-dioxopyrazolidine derivatives of the v3! Formula I by contacting a phenyl hydrazone derivative represented by the formula,

B1 (II) wherein R R R R and R are as defined above in the Formula I, with a malonic acid derivative having the formula,

C O OH Rz-CH C O OH (III) wherein R is as defined above, or its reactive derivative. And further, the present invention is concerned with a process for producing 3,5-dioxopyrazolidine derivatives of the Formula I by reacting the phenylhydrazone derivatives of the Formula II with an organic acid of the formula,

RqCOOH (IV) wherein R represents an alkyl group having up to 3 carbon atoms, or its reactive derivative, and then contacting the resulting N ,N -diacyl phenylhydrazine derivative of the formula,

wherein R R R R R and R are as defined above; with a malonic acid derivative of the Formula 111.

In accordance with the present invention, the process producing 3,5 dioxopyrazolidine derivatives of the Formula I may be shown by the following reaction schema;

All of these processes proceed smoothly and give the objective products in high yields, and therefore these procedures are quite advantageous, in practice.

An object of the present invention is to provide a novel process for preparing 3,5-dioxopyrazolidine derivatives of the formula I.

The process of the present invention is carried out in being accompanied with migration of a double bond of a hydi razone derivative to 3,5-dioxo pyrazolidine derivative. The migration of a double bond of the hydrazone and acylation of N and N -positions of the hydrazone derivative may proceed at the same time, and the reaction method is novel and has not heretofore been described in any other literature.

These 3,5-dioxopyrazolidine derivatives of the Formula 1, according to this invention, may be prepared by reacting phenylhydrazone derivatives of the Formula II with malonic acid derivatives of the Formula III, or their reactive derivatives such as, for example, alkyl esters, acid halides, mixed acid anhydrides, preferably in the presence of an appropriate agent. These agents for acylation include, for example, sodium methoxide, sodium ethoxide, potassium ethoxide, potassium tertiary butoxide, sodium amide, potassium amide and the like, and sodium ethoxide or sodium methoxide is preferable for this reaction. The agent is used in the stoichiometric amount or more. Benzene, toluene, xylene, dioxane and the like are used as solvents in these reactions, but a solvent having lower boiling point may be preferably changed to an other solvent having a higher boiling point by distillation in order to complete the reaction in a shorter time. The reaction temperature is within the range of a room temperature to the boiling point of the solvent, preferably -150 C.

After completion of reaction, the aftertreatment may be readily carried out. The reaction mixture is extracted with an appropriate solvent after acidifying with aqueous mineral acid, and the solvent is removed to dryness, and then the desired 3,5-dioxopyrazolidine derivative may be isolated as crude product. This product is further purified, if desired, by recrystallization from a suitable solvent such as ethanol, benzene or the like.

According to the process of the present invention, there are produced such 3,5-dioxopyrazolidine derivatives as shown below.

1-phenyl-2-styryl-4-n-butyl-3 ,5 -dioxopyrazolidine 1-phenyl-2-styryl-4-n-pentyl-3,S-dioxopyrazolidine 1-phenyl-2-styryl-4-isobutyl-3,S-dioxopyrazolidine 1-phenyl-2-styryl-4-n-propyl-3,S-dioxopyrazolidine 1- p-tolyl)-2-styryl-4-n-buty1-3,S-dioxopyrazolidine 1-(p-chlorophenyl)-2-styryl-4-n-butyl-3,5-

dioxopyrazolidine 1- (p-methoxyphenyl)-2-styryl-4-n-butyl-3,5-

dioxopyrazolidine l-phenyl-Z- (p-chlorostyryl)-4-n-butyl-3,5-

dioxopyrazolidine l-phenyl-Z- (p-methylstyryl -4-n-b utyl-3,5-

dioxopyrazolidine 1-pheny1-2-(p-methoxystyryl) -4-n-butyl-3,5-

dioxopyrazolidine 1-phenyl-2- a-methylstyryl -4n-buty1-3,5-

dioxopyrazolidine 1-phenyl-2- (fi-methylstyryl -4-n-butyl-3,5-

dioxopyrazolidine 1-phenyl-2- (u,fi-dimethylstyryl)-4-n-butyl-3,5-

dioxopyrazolidine 1-phenyl-2- (m-chlorostyryl) -4-n-butyl-3,5-

dioxopyrazolidine l-phenyl-2-(o-chlorostyryl)-4-n-butyl-3,5-

dioxopyrazolidine 1-phenyl-2- (m-methylstyryl)-4-n-butyl-3,5

dioxopyrazolidine l-phenyl-Z- (o-methylstyryl)-4-n-butyl-3,5-

dioxopyrazolidine 1-phenyl-2- (p-methylstyryl)-4-n-propyl-3,5-

dioxopyrazolidine l-phenyl-Z- (p-methylstyryl)-4-n-pentyl-3,5-

dioxopyrazolidine 1-phenyl-2-(3', -methylenedioxystyryl)-4-n-propyl-3,5-

dioxopyrazolidine l-phenyl-Z-(3',4'-dimethoxystyryl)-4-n-butyl-3,5-

dioxopyrazolidine 1-pheny1-2-(3 ',4'-dimethoxystyryl) -4-n-propy1-3,5-

dioxopyrazolidine l-phenyl-2- 3',4-dimethylstyryl) -4-n-butyl-3,5-

dioxopyrazolidine 1-pheny1-2-(3',4'-dimethylstyryl)-4-n-propyl3,5

dioxopyrazolidine l-phenyl-Z-(2'-methoxy-3-methylstyryl)-4-n-butyl-3,5-

dioxopyrazolidine 1-phenyl-2-(2'-methoxy- '-methylstyryl)-4-n-propyl-3,5-

dioxopyrazolidine 1-phenyl-2-(2-rnethoxy-5'-methylstyryl)-4-n-butyl-3,5-

dioxopyrazolidine 1-phenyl-2- 2'-methoxy-5'-methylstyryl) -4-n-propy1-3,5-

dioxopyrazolidine l-phenyl-Z- 3',4',5'-trimethoxystyryl) -4-n-buty1-3,5-

dioxopyrazolidine 1-phenyl-2-(3',4,5'-trimethoxystyryl)-4-n-propyl-3,5-

dioxopyrazolidine 1-p-tolyl-2- (3 ,4'-metl1ylenedioxystyry1) -4-n-butyl-3,5-

dioxopyrazolidine 1-p-tolyl-2-(3',4'-methylenedioxystyryl)-4-n-propy1-3,5-

dioxopyrazolidine 1-p-tolyl-2-(3',4'-dimethoxystyryl)-4-n-butyl-3,5-

dioxopyrazolidine 1-p-toly1-2-(3',4-dimethoxystyryl)-4-n-propyl-3,5-

dioxopyrazolidine 1-ptoly1-2-(3,4-dimethylstyryl)-4-n-butyl-3,5-

dioxopyrazolidine 1-p-tolyl-2-(3',4'-dimethylstyryl)-4-n-propyl-3,5-

dioxopyrazolidine 1-p-tolyl-2- 2'-methoxy-3'-methylstyryl) -4-n-butyl-3,5-

dioxopyrazolidine 1-p-tolyl-2-(2-methoxy- 'methylstyryl)-4-n-propyl-3,5-

dioxopyrazolidine 1-p-to1yl-2-(2'-methoxy-5-methylstyry1)-4-n-butyl-3,5-

dioxopyrazolidine 1-p-to1yl-2-(2'-methoxy-5'-methylstyry1)-4-n-propyl-3,5-

dioxopyrazolidine l-p-tolyl-2-(3',4',5'-trimethoxystyryl)-4-n-butyl-3,5-

dioxopyrazolidine l-p-tolyl-Z-(3,4,5'-trimethoxystyryl)-4-n-propyl-3,5-

dioxopyrazolidine l-p-chlorophenyl-Z- 3 ',4'-methylenedioxystyryl -4-nbutyl-3,S-dioxopyrazolidine l-p-chlorophenyl-Z-(3',4-methylenedioxystyryl)-4-npropyl-3,S-dioxopyrazolidine 1-p-chlorophenyl-2- 3', -dimethoxystyryl) -4-n-butyl- 3,5-dioxopyrazolidine l-p-chlorophenyl-Z-(3,4'-dimethoxystyryl)-4-n-propyl- 3,5-dioxopyrazolidine 1-p-chlorophenyl-2-(3',4-dimethylstyryl)-4-n-butyl- 3,5-dioxopyrazolidine l-p-chlorophenyl-Z-(3,4-dimethylstyryl)-4-n-propyl- 3,5-dioxopyrazolidine 1-p-ch1orophenyl-2-(2-methoxy-3-methylstyryl)-4-nbutyl-3,S-dioxopyrazolidine 1-p-chlorophenyl-2-(2-methoxy-3'-methylstyryl)-4-npropyl-3,S-dioxopyrazolidine 1-p-chlorophenyl-2-(2'-methoxy-5'-methylstyryl)-4-nbutyl-3,S-dioxopyrazolidine 1-pch1oropheny1-2-(2-methoxy-5'-methylstyryl) -4-npropyl-3,S-dioxopyrazolidine 1-pchloropheny1-2-( 3 ',4',5'-trimethoxystyryl) -4-nbutyl-3,S-dioxopyrazolidine l-p-chlorophenyl-L(3',4,5'-trimethoxystyryl)-4-n propyl-3,S-dioxopyrazolidine And further, the present invention provides a process for preparing 3,5-dioxopyrazolidine derivatives of the Formula I from N ,N -diacyl phenylhydrazine derivatives of the Formula V, which is obtained by reacting phenylhydrazone derivatives of the Formula II with an organic acid of the Formula IV.

Phenylhydrazone derivatives of the Formula II may be acylated by contacting with an organic acid or its reactive derivative of the Formula IV, and the reaction is accompanied with migration of a double bond of a hydrazone type to a hydrazine type represented by the Formula V.

The suitable reactive derivatives of the organic acid include, for example, acetic acid anhydride, propionic acid anhydride, benzoic acid anhydride, acetyl chloride, acetyl bromide and the like. Acetic acid anhydride is most preferable.

This reaction progresses at a temperature within the range of 50140 C. preferably in the presence of a small amount of catalyst, for example, p-toluenesulfonic acid, hydrochloric acid, borontrifluoride, aluminum chloride, zinc chloride and the like. p-Toluenesulfonic acid is most preferable.

According to the above process, the following phenylhydrazine derivatives are produced.

N ,N -diacetyl-N -styrylphenylhydrazine N ,N -diacetyl-N (p-methylstyryl phenylhydrazine N ,N diacetyl-N p-methoxystyryl phenylhydrazine N N -diacetyl-N (p-chlorostyryl phenylhydrazine N ,N -diacetyl-N o-methylstyryl) phenylhydrazine N ,N -diacetyl-N m-methylstyryl) phenylhydrazine N ,N -diacetyl-N 3 ,4-dimethylstyry1)phenylhydrazine N ,N diacetyl-N 3,4-dimethoxystyryl phenylhydrazine N ,N -diacetyl-N 3,4-methylenedioxystyryl phenylhydrazine N ,N -diacetyl-N 2-methoxy-3-methylstyryl phenylhydrazine N ,N -diacetyl-N (Z-methoxy-S-methylstyryl phenylhydrazine N ,N -diacetyl-N -styryl-p-methylphenylhydrazine N N -diacetyl-N (p-methylstyryl -p-methylphenylhydrazine N ,N -diacety1-N -(o-methylstyryl)-p-methylphenylhydrazine N ,N -diacetyl-N (p-methoxystyryl -p-methylphenylhydrazine N ,N -diacetyl-N (p-chlorostyryl -p-methylphenylhydrazine N ,N -diacetyl-N (p-methylstyryl -p-chlorophenylhydrazine N ,N -diacetyl-N (o-methylstyryl -p-chlorophenylhydrazine N ,N -diacetyl-N (p-methoxystyryl -p-chlorophenylhydrazine These products may be readily isolated from the reaction systems, but the isolation is not necessary for carrying out the next process, which reacts with a malonic acid derivative of the Formula III or its reactive derivative. 3,5-dioxopyrazolidine derivatives of the Formula I, according to this invention, may be prepared by reacting N ,N -diacylphenylhydrazine derivatives of the Formula V with malonic acid derivatives of the Formula III or their reactive derivatives, preferably in the presence of an appropriate agent, such as sodium methoxide, sodium ethoxide, potassium ethoxide, potassium tertiary butoxide, sodium amide, potassium amide and the like. Benzene, toluene, xylene, dioxane and the like are used as solvents in these reaction. The reaction temperature is within the range of room temperature to the boiling point of the used solvent and the reaction proceeds much more smoothly in general.

After completion of reaction, the aftertreatment may be readily carried out. The reaction mixture is extracted with an appropriate solvent after acidifying with an aqueous mineral acid, and the solvent is removed to dryness, and then the desired 3,5-dioxopyrazolidine derivative may be isolated as crude product. This product is further purified, if desired, by recrystallization from a suitable solvent such as ethanol, benzene, or the like.

According to this process, there are produced the 3,5- dioxopyrazolidine derivatives mentioned above, which are prepared from hydrazone derivatives of the Formula II.

The phenyl-hydrazone derivatives of the Formula II, which are the initial starting material in this process, are prepared, for example, by reacting a corresponding carbonyl derivative of the Formula VI,

2-styryl-4-n-amyl-3,5-dioxopyrazolidine, M.P. 141 -142 5 C. Recrystallization from ethanol gives 13 g. of the prod- (Vn) uct having M.P. 142l43 C.

wherein R is as defined above, or its salt.

Among these novel 3,5-dioxopyrazolidine derivatives of the present invention described before, there are a few useful compounds, which indicate not only excellent antiinflammatory action but also possess comparatively low toxicity. The many compounds of this invention are low in toxicity, and even when over 200 mg./kg. of these compounds are orally administrated to each of rat and mouse, they scarcely show toxic symptoms and occult bleeding is negative in feces thereof. Nevetheless, the activities of these compounds are much higher than those of 1,2-diphenyl-3,5-dioxo-4-n-butylpyrazolidine (phenylbutazone) and oxyphenbutazone. Therefore, the therapeutic ratios of the compounds of the present invention are far greater than any other drugs. Therefore, these compounds are markedly valuable in practical use.

The therapeutic ratios of these compounds of the present invention, and 1,2 diphenyl 3,5 dioxo-4-n-butylpyrazolidine (phenylbutazone) are given in the following table.

It has found that these compounds also have comparatively potent analgesic activities shown by Haifners method, and antipyretic activities in a pyrogen test.

This invention is further disclosed in the following examples of preferred embodiments thereof, which are presented for purposes of illustration and are not intended to 'limit the scope of the invention.

EXAMPLE 1 0 To a solution of 3 g. of metallic sodium dissolved m ml. absolute ethanol are added 15 g. of phenylacetaldehyde phenylhydrazone and a solution of 17 g. of diethyl n-amylma'lonate in 150 ml. xylene. The mixture is heated at 100 C. for 3 hours and then at C. for 14 hours with stirring. After cooling, the reaction mixture is poured into water on ice cooling, and acidified with aqueous hydrochloric acid. The organic layer is separated and the aqueous layer is extracted with ethylacetate. The ethylacetate layer is combined with the organic layer, washed with water, dried over sodium sulfate and evaporated under reduced pressure. The oily residue is crystallized on treatment with ethanol to give l-phenyl- By a method similar to that mentioned above, following compounds are prepared from a corresponding phenylacetaldehyde phenylhydrazone derivative.

1-phenyl-2-styryl-4-n-butyl-3,S-dioxopyrazolidine, M.P.

1-p-tolyl-2-styryl-4-n-butyl-3,5-dioxopyrazolidine, M.P.

M.P. 147l48 C. 1-phenyl-2-(3,4-methylenedioxystyryl)-4-n-butyl-3,5-

dioxopyrazolidine, M.P. -146 C. 1-p-tolyl-2-(3',4'-methylenedioxystyryl)-4-n-butyl-3,5-

dioxopyrazolidine, M.P. 133-134 C. l-p-chzlorophenyl-Z-(S',4-methylenedioxystyryl)-4-nbutyl-3,S-dioxopyrazolidine, M.P. l55156 C. 1-phenyl-2-(p-chlorostyryl)-4-n-butyl-3,S-dioxopyrazolidine, M.P. C. 1-p-tolyl-2-(p-chlorostyryl)-4-n-butyl-3,S-dioxopyrazolidine, M.P. l78179C.

The present inventors prepared many other 3,5-dioxopyrazolidine derivatives than the compounds shown in the aforesaid table and evaluated the pharmaceutical effects thereof by animal tests.

The present inventors have found that many 3,5-dioxopyrazolidine derivatives of the Formula I, which are prepared by the present invention, are superior to 1,2-- diphenyl-3,5-dioxo-4-n butylpyrazo'lidine (phenylbutazone) in the therapeutic ratios thereof and has a great practical value.

1-p-chlorophenyl-2-(p-chlorostyryl)-4-n-butyl-3,5-dioxopyrazolidine, M.P. 172173 C.

l-phenyl-Z-(3',4'-dimethoxystyryl)-4-n-butyl-3,5-dioxopyrazolidine, M.P. 108109 C.

70 1-p-tolyl-2-(3',4'-dimethoxystyryl)-4-n-butyl-3,5-dioxopyrazolidine, M.P. l20-l21 C.

1-p-chloropheny1-2-( 3 ',4-dimethoxystyryl -4-n-butyl- 3,5-dioxopyrazolidine, M.P. 123 -124 C.

l-phenyl-2-(o-methoxystyryl)-4-n-butyl-3,5-dioxopyrazolidine, M.P. 110-111 c.

1-p-ch10rophenyl-2-styryl-4-n-butyl-3,S-dioxopyrazolidine,

1- (p-methoxyphenyl -2- (fl-methyl-styryl )-4-n-butyl-3,5-

dioxopyrazolidine 1- p-methoxyphenyl) -2-( a,,8-dimethylstyryl) -4-n-butyl- 3,5 -dioxopyrazolidine 1- (p-methoxyphenyl) -2- (m-chlorostyryl -4-n-butyl-3 ,5

dioxopyrazolidine 1- (p-methoxyphenyl -2- (o-chlorostyryl -4-n-butyl-3,5-

- dioxopyrazolidine 1- p-methoxyphenyl) -2- (m-methylstyryl) -4n-butyl-3,5-

dioxopyrazolidine 1* (p-methoxyphenyl) -2- (o-methylstyryl) -4-n-butyl-3 ,5

dioxopyrazolidine 1- (p-methoxyphenyl) -2- (p-methylstyryl -4-n-propyl-3,5-

dioxopyrazolidine 1- (p-methoxyphenyl -2- ('pmethylstyryl -4-n-pentyl-3,5-

dioxopyrazolidine 1- (p-methoxyphenyl) -2- o-methoxystyryl) -4n-butyl-3 ,5

dioxopyrazolidine 1- (p-methoxyphenyl -2- (p-isopropylstyryl -4-n-butyl- 3,5 -dioxopyrazolidine 1- p-methoxyphenyl) -2- (p isopropylstyryl) -4-n-propyl- 3,5-dioxopyrazolidine 1- (p-methoxyphenyl -2- (p-nitrostyryl -4-n-butyl-3 ,5

dioxopyrazolidine 1- p-methoxyphenyl )-2- (p-ethylstyryl) -4-n-butyl-3 ,5

dioxopyrazolidine 1- (p-chlorophenyl -2- (a-methylstyryl -4n-butyl-3,5-

dioxopyrazolidine 1- (p-chlorophenyl) -2-(,B-methylstyry1 )-4-n-butyl-3,5-

dioxopyrazolidine 1- (p-chlorophenyl -2- (a,;8-dimethy1styryl) -4-n-butyl- 3,5 -dioxopyrazolidine 1- (p-chlorophenyl -2- (m-chlorostyryl) -4-n-butyl-3,5-

dioxopyrazolidine 1- (p-chlorophenyl) -2- o-chloro styryl -4-n-butyl-3 ,5

dioxopyrazolidine 1- (p-chlorophenyl) -2- (m-methylstyryl -4n-butyl-3,5-

dioxopyrazolidine 1- (p-chlorophenyl) -2- (o-methylstyryl -4-n-buty1-3,5-

dioxopyrazolidine 1- p-chlorophenyl) -2- (p-methylstyryl) -4-n-propyl-3,5-

dioxopyrazolidine 1- p-chlorophenyl) -2- (p-methylstyryl) -4-n-pentyl-3 dioxopyrazolidine What is claimed is:

1. A process for preparing 3,5-dioxopyrazolidine derivatives represented by the formula,

wherein R signifies a hydrogen atom, a halogen atom, a nitro group, a lower alkyl group, a lower alkoxy group; R signifies an alkyl group having up to 6 carbon atoms; R and R each signifies a hydrogen atom, a lower alkyl group, a phenyl group or a halogen-, (l -Q alkylor C -C alkoxy-substituted benzene group; R and R each signifies a hydrogen atom, a halogen atom, a nitro group, a lower alkyl group, a lower alkoxy group, a trifluoromethyl group, or a C -C alkyl-substituted amino group; provided that R and R may form optionally methylenedioxy or ethylenedioxy together with the adjacent phenyl group, which process comprises reacting in the presence of a base selected from the group consisting of alkali metal alcoholates, alkali metal amides and alkali metal hydroxides and in the absence of a solvent or in the presence of a solvent selected from the group consisting of benzene, toluene, xylene and dioxane at a temperature from to a phenylhydrazone derivative represented by the formula,

Rs R5 wherein R signifies a hydrogen atom, a halogen atom, a nitro group, a lower alkyl group, a lower alkoxy group; R signifies an alkyl group having up to 6 carbon atoms; R and R each signifies a hydrogen atom, a 'lower alkyl group, a phenyl group or a halogen-, C -C alkylor C -C alkoxy-substituted benzene group; R and R form methylenedioxy or ethylenedioxy together with the adj aoent phenyl group.

References Cited UNITED STATES PATENTS 3,547,916 12/1970 Schatz et al. 260-240 D FOREIGN PATENTS 732,820 6/1955 England 2603 10 B OTHER REFERENCES Yamamoto et al.: Journal of Med. Chem., vol. 13, pp. 292 to 295 (1970).

Wiley et al.: Pyrazolones, Pyrazolidones land Derivatives, p. 488 (references) added, Interscience Publishers, NY. (1964).

JOHN D. RANDOLPH, Primary Examiner US. Cl. X.R.

2603l0 A, 340.3, 340.5, 562 H, 566 B 

